Oxidized low-density lipoprotein (OxLDL) is believed to play an important role in the pathogenesis of atherosclerosis.1 Unregulated uptake of OxLDL by macrophages within the arterial wall leads to foam cell formation followed by development of the fatty streak that is typical of early atherosclerotic lesions.1,2 Macrophages express a number of scavenger receptors that bind OxLDL.3-6 Among these is CD367 which recent evidence suggests may be an important scavenger receptor involved in the uptake of OxLDL by macrophages and may have a significant role in foam cell formation in vivo. The epitope(s) responsible for recognition of OxLDL by CD36, and other scavenger receptors, have not been clearly defined. Identification of the structural features on OxLDL that are responsible for recognition by CD36 could provide a template for the design of compounds with highly specific interactions with these macrophages and other immune system components with the eventual goal of finding new strategies for the treatment of atherosclerosis.
A wide variety of biologically active phospholipid oxidation products can be formed upon oxidation of LDL.8,9 For example, oxidation of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (PAPC, 1) yields an oxidized phospholipid by-product, 1-palmitoyl-2-(5′-oxo)valeroyl-sn-glycero-3-phosphoryl-choline (POVPC, 2), with a reactive aldehyde at the ε-carbon (Scheme 1).

This reactive “phospholipid core aldehyde” in turn forms adducts with lysine residues of apoB, or other proteins, as well as other amine-containing phospholipids.10-12 
Previous work has shown that binding of OxLDL to CD36 is mediated by oxidized phospholipids (OxPLs).13-15 In addition, a natural autoantibody against OxLDL, designated E06, was isolated from hypercholesteremic apolipoprotein E (apoE)-deficient mice and was shown to block the uptake of OxLDL by macrophages.16 Detailed studies of POVPC and variously modified conjugates revealed that the phosphorylcholine head group is essential for binding to CD36 and for antigenicity for E06, but that this activity required prior conjugation of the sn-2 aldehyde with a peptide or protein to yield a Schiff's base.17,18 Initial experiments demonstrated that Schiff's base conjugates of POVPC with bovine serum albumin (BSA) inhibited binding of OxLDL to CD36. As illustrated in FIG. 1A, a POVPC conjugate with a short peptide chain containing a single lysine residue for imine formation also inhibited binding.
The aqueous solution of the conjugate slowly lost its activity in the assay as the imine hydrolyzed. In an effort to improve the aqueous stability of the Schiff's base conjugate, the imine intermediate was reduced to the corresponding amine with sodium cyanoborohydride. This compound retained its competitive binding activity but was still prone to a slow decomposition in aqueous solution, presumably from intramolecular O′N-acyl transfer, as illustrated in FIG. 1B.
There is therefore a need for a stable compound with high selectivity for these specific antibodies and macrophage receptors that could be used for the treatment of atherosclerosis. Instability of both the imine and amine adducts means that the compounds generated to this point do not meet this goal.